ES2310942T3 - TOLTERODINE ADMINISTERED BY TRANSDERMIC AS AN ANTI-MUSCARINIC AGENT FOR THE TREATMENT OF HYPERACTIVE BLADDER. - Google Patents

Abstract

The present invention is drawn to set of formulations of at least one compound selected from tolterodine, salts thereof, prodrugs thereof and/or metabolites thereof, wherein in the set of formulations contains at least one device for transdermal administration and at least one formulation for oral, sublingual, buccal, nasal, pulmonary, rectal and/or other transmucosal administration, in order to achieve an effect against overactive bladder and/or symptoms associated with this condition. The present invention is further drawn to methods of treating an overactive bladder with the formulations.

Description

Tolterodine administered transdermally as an anti-muscarinic agent for the treatment of overactive bladder.

Field of invention

This invention relates to a device for transdermal administration of tolterodine, optionally salts that include it, and the tolterodine metabolite (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenyl-propanamine;  and to the use of tolterodine, optionally salts that include it and the tolterodine metabolite (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenyl-propanamine,  for the manufacture of a medicine to be administered via transdermal to achieve an effect against the bladder hyperactive

Background

Tolterodine is an effective and safe compound. for the treatment of overactive bladder. The synthesis of tolterodine and its usefulness for the treatment of overactive bladder It is described in US 5,382,600 (Pharmacia & Upjohn AB). An optimal efficacy / side effects profile is obtained at an oral dosage of 1 or 2 mg twice daily. High potency (and therefore clinically serum concentrations low effective) and the relatively short half-life (approximately 2 hours in the majority of the population, that is, in extensive metabolizers, EM) makes tolterodine a possible candidate for a patch formulation. Additional properties that support the viability of the patch principle are that the bladder hyperactive is a syndrome that can benefit from a profile of flat serum concentration and it is known that the compounds Anti-muscarinics do not cause tolerance.

Tolterodine has a molecular weight of 325.0 and 475.6 in the form of the tartrate salt. The enantiomeric purity is of > 99%. The value of pK_a is 9.87 and the water solubility is approximately 11 mg / ml (room temperature). The coefficient of distribution (Log P) between n-octanol and phosphate buffer a pH 7.32 is 1.83.

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one

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Tolterodina, PNU-200583

N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine.

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The main metabolic pathway for metabolism Tolterodine is mediated by cytochrome P450 2D6 which leads to the formation of DD 01, (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine.  The metabolite DD 01 (also indicated 5-HM) has a pharmacological profile similar to tolterodine - see Nilvebrant L, Gillberg P-G, Sparf B. "Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine ". Pharmacol. Toxicol. (1997) 81: 195-207. For the similarity with tolterodine in the pharmacological profile, see Brynne N, Dalen P, Alvan G, Bertilsson L and Gabrielsson J, Clin Pharmacol Ther 1998 (63): 529-39. A minority part of the population (the bad metabolizers, PM) is devoid of 2D6 isoenzyme and these subjects showed higher concentrations of tolterodine but no measurable levels of DD 01.

Differences in the pharmacokinetic profile of Tolterodine in MS and PM are not reflected in the clinical response, since exposure to the sum of unbound tolterodine and DD 01 is Similar in both groups. Therefore the same can be applied oral dosing regimen regardless of phenotype. He Transdermal concept is based on the same premise.

The present invention encompasses administration. transdermal tolterodine isomer R.

Prior art

Document US 5,382,600 mentioned previously does not describe the transdermal administration of tolterodine

WO 98/03067 describes the S isomer Tolterodine Claim the transdermal administration of said S isomer to treat urinary avoidance disorders. Excludes explicitly transdermal administration of the R isomer or of a racemic mixture. Either way, WO 98/03067 it only shows the usefulness of the oral dosage form of said S isomer. Transdermal administration thereof only. it is suggested, as parenteral, vaginal and aerosol routes, without No sample of utility.

WO 93/23025 and WO 96/23492 describe the transdermal administration of oxobutinin and of (S) -oxybutynin or (S) -desethyloxobutinin respectively to treat neurogenic bladder disorders It should be appreciated that in agreement with WO 93/23025, an enhancer is required to administer oxobutinin transdermally. Oxobutinin has a chemical structure that is totally different from that of tolterodine WO 95/10270 describes the administration transdermal S-terodiline to treat urinary incontinence WO 96/27375 describes the transdermal administration of dextromethorphan or dextrorphan for treat urinary incontinence WO 97/25984 describes transdermal administration of a nitric oxide substrate synthase to treat the symptoms of urinary incontinence. He WO 98/00141 describes the transdermal administration of (S) -anthomerically enriched enrichomerically enriched to treat urinary incontinence. Either way, none of the above substances has no similarity to the tolterodine

Therefore, the present invention, as further described below, it is both new and Inventive about the prior art.

Objectives of the invention

A transdermal formulation with tolterodine as active ingredient will provide an alternative to tablet formulation for the oral route. There's a possibility that due to the more constant serum concentrations during a dosage interval, side effects compared With immediate-release tablets, they can be reduced additionally, while maintaining clinical efficacy.

The transdermal delivery route prevents risk of dose discharge with oral administration forms of prolonged release In addition, patient compliance is will increase since

- elderly people and children can have Difficulties swallowing oral dosage forms

- patients can visually observe that they are taking their medication (contrary to not remembering if you have swallowed your tablet)

- administration is possible once a day

- administration of several days is possible with a patch

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Globally, these effects increase the advantages and compliance by patients.

Therefore, a first objective of the present invention is to provide a device for transdermal administration of tolterodine, optionally salts that they include it and the tolterodine metabolite (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine,  to achieve an effect against overactive bladder (which includes detrusor instability, detrusor hyperreflexia, frequency incontinence, bladder tenesmus or need imperious). Administration can be to a human being or to a animal. Administration can be done without the use of a enhancer

A second objective of the invention is provide the use of a compound that has an effect against the overactive bladder, which comprises tolterodine for the manufacture of a composition to be administered transdermally to treat the overactive bladder or symptoms associated with this condition: it is say incontinence due to bladder tenesmus, frequency, nocturia and imperative need.

Other objects of the invention will be achieved. evident to those skilled in the art, and also others objectives will become apparent from now on.

Summary of the invention

The present invention relates to the transdermal administration of tolterodine, optionally salts that they include it and the tolterodine metabolite (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine  to achieve an effect against the overactive bladder. This effect is achieved primarily through the systemic effect of Tolterodine Either way, others are not excluded Actions.

Brief description of the drawings and tables

Figures 1A-1D are drawings Schematics of different types of devices for supply transdermal drugs.

Figure 2 is a diagram showing the in vitro skin filtration of tolterodine base from different solvents according to Example 1.

Figure 3 is a diagram showing in vitro skin filtration of tolterodine base through different membranes according to Example 2.

Figure 4 is a diagram showing in vitro dissolution of tolterodine base from different transdermal systems according to Example 3.

Figures 5, 6, 7, 8 and 9 are diagrams showing the in vitro dissolution of tolterodine base from different transdermal systems according to Example 7.

Figures 10, 11, 12, 13 and 14 are diagrams showing the in vitro skin filtration of tolterodine base from different transdermal systems according to Example 8.

Figure 15 is a diagram showing the in vitro dissolution of tolterodine base from different transdermal systems according to Example 10.

Figure 16 is a diagram showing the in vitro skin filtration of tolterodine base from different transdermal systems according to Example 11.

Figure 17 is a diagram showing the in vitro dissolution of tolterodine base from different transdermal systems according to Example 13.

Figures 18 and 19 are diagrams showing the in vitro dissolution of tolterodine L-tartrate and tolterodine base from different transdermal systems according to Example 16.

Figures 20 and 21 are diagrams showing the in vitro skin filtration of tolterodine and tolterodine base L-tartrate from different transdermal systems according to Example 17.

Figure 22 is a diagram showing the in vitro dissolution of tolterodine base from different transdermal systems according to Example 20.

Figure 23 is a diagram showing the in vitro skin filtration of tolterodine base from different transdermal systems according to Example 21.

Figure 24 is a diagram showing the in vitro dissolution of DD 01 from Durotak 387-2516 according to Example 26.

Figure 25 is a diagram showing the in vitro skin filtration of DD 01 from Durotak 387-2516 according to Example 27.

Figure 26 is a diagram showing the in vitro dissolution of tolterodine base from multilaminated patches according to Example 30.

Figure 27 is a diagram showing the in vitro skin filtration of tolterodine base from multilaminated patches according to Example 31.

Figure 28 is a diagram showing in vitro dissolution of tolterodine base from a silicone adhesive according to Example 33.

Figure 29 is a diagram showing the in vitro skin filtration of tolterodine base from a silicone adhesive according to Example 34.

Figure 30 is a diagram showing the in vitro skin filtration of tolterodine base from patches where a non-occlusive membrane has been used as reinforcement according to Example 36.

Figure 31 is a diagram showing the in vitro dissolution of tolterodine base from a reservoir patch according to Example 38.

Figure 32 is a diagram showing the in vivo data of a bioavailability study according to Example 39.

Table 1 is an overview that shows different influence factors on the ability to control The speed of a transdermal device.

Table 2 is an overview that shows Different formulations of tolterodine base according to the Example 5 and 6.

Table 3 is an overview that shows different transdermal formulations with tolterodine base according to Example 9.

Table 4 is an overview that shows different transdermal formulations with tolterodine base according to Example 12.

Table 5 is an overview that shows different transdermal formulations with tolterodine base according to Example 14 and 15.

Table 6 is an overview that shows the stability data of different transdermal formulations with tolterodine base according to Example 18.

Detailed description of the invention

Transdermal drug delivery may be obtained from topical products such as ointments or creams or from transdermal devices. The present invention relates to administration by transdermal devices defined in the claims, which are usually called patches transdermal

Devices that can be used as transdermal patches can be categorized in many ways different. A comprehensive categorization of devices transdermal is found in Wick S. Developing A Drug-In-Adhesive Design For Transdermal Drug Delivery. Adhe Age 1995; 38: 18-24.

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Wick essentially divides the devices transdermal in the following four main groups:

- the type deposit , in which the drug is placed in a liquid or a gel and is supplied through a membrane that moderates the speed to the skin;

- the matrix type , in which the drug is placed within a non-adhesive polymeric material, typically a hydrogel or soft polymer;

- the drug type in adhesive , in which the drug is placed inside an adhesive polymer;

- the multi-laminate type , which is similar to the adhesive drug design but incorporates an additional layer of pressure sensitive adhesive that covers the entire device and fixes it to the skin. A multi-laminated membrane can also be incorporated as shown in Fig. 1B.

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The previous four main types of Transdermal devices are schematically illustrated in Fig. 1A-1D.

A fifth important type, not mentioned by Wick, is the iontophoretic type , which is the predominant mechanism for electrically assisted transdermal delivery. When the iontophoretic type is used, an electric potential gradient is used to transfer the drug through the skin - see additionally, for example, Singh P et al. Iontophoresis in Drug Delivery: Basic Principles and Applications. Crit Rev Ther Drug Carrier Syst 1994; 11: 161-213.

Apart from this, electroporation , electroosmosis , electroincorporation and jet injection can be used.

Electroporation is the creation of transient aqueous pores in lipid bilayer membranes by the application of a short electrical pulse (msecond) (Prausnitz MR et al. Proc Int Symp Control. Rel Biact Mater 1993; 20: 95-96). Using electroporation will alter skin permeability so that resistance to drug transport will be reduced. Electroporation has been used in the supply of transdermal drugs by coupling them with iontophoresis (Bommannan D et al. Pharm Res 1994; 11: 1809-1814, Prausnitz MR et al. Proc Na Acad Sci USA 1993; 90: 10504-10508, and Riviere JE et al. J Controlled Release 1995; 36: 299-233). In these cases, a short pulse (few milliseconds) of high voltage alters the skin permeability so that subsequent iontophoresis is facilitated.

With electroosmosis the electric field creates a convective flow of water that allows hydrophilic compounds to be transported. Very related to electroporation is electroincorporation but here the particles (microspheres, liposomes) are replaced on the surface of the skin and subsequent high-voltage electrical pulses are used (Riviere JE and Heit MC. Pharm Res 1997; 14: 687-697 ).

Jet injection can be used for both powders as for liquids (Muddle AG et al. Proc Int Symp Control. Rel Biact Mater 1997; 24: 713-714, and Seyam RM et al. Urology 1997; 50: 994-998). Using the injection by jet can be given a drug by a painless injection without needle.

The previous division into groups is not very strict since variations and combinations of each can be foreseen one. So that a device of type Multi-laminate can encompass a device with many layers in a sandwich construction, such as the drug in one layer, excipients such as enhancers in one layer additionally, a membrane in another layer and an adhesive in another layer. Or it could be composed of several layers of drug in adhesive or combinations of the previous layers.

The liquid or gel used in the type device previous reservoir could be hydrophilic or lipophilic, such as water, alcohols, mineral oils, silicone fluids, various copolymers, such as ethylene vinyl acetate, vinyl acetate or polyvinyl alcohol / polyvinyl pyrrolidone. The deposit It can also include dyes, inert fillers, diluents, antioxidants, anti-irritants, anti-sensitizers, enhancers of the filtration, stabilizers, solubilizing agents and other agents pharmacologically inactive pharmacists that are well known in the technique

The adhesives used are generally three types, which the rubber type, which includes among other polyisobutylenes, the acrylate type and the silicone type. The adhesives can be chemically modified, and can have a wide range of molecular weights Various types of adhesive could be added to the adhesive excipients such as fillers, stabilizers, plasticizers, buffering agents, filtration enhancers, retarders of filtration, anti-irritants, antisensitizers, solubilizing agents and other ingredients Pharmacists who are well known in the art.

Polymeric films that can be used for manufacture the speed moderating membrane include, without limitation, those comprising low and high polyethylene density, copolymers of ethylvinyl acetate and other polymers adequate.

The reinforcing layer serves the purposes of prevent the passage of the drug and / or the environmental humidity through the outer surface of the patch, and also to provide support to the system, where it is needed. Additionally the reinforcement layer can provide occlusion, and therefore increases the speed of supply of the drug in the skin. The reinforcing layer can be chosen in such a way that the final product is attractive to users, whether children, adults, the elderly or other groups of consumers. The reinforcement layer is impermeable to the passage of tolterodine or inactive ingredients that are present in the formulation and can be flexible or non-flexible. The materials Suitable include, without limitation, polyester, terephthalate polyethylene, some kind of nylon, polypropylene, films Metallic polyester, polyvinylidene chloride and foil aluminum.

The release liner may be Made of the same materials as the reinforcement layer.

It is well known in the art that the properties of the skin as such influence the filtration of the drug through of the skin in the systemic circulation. Therefore it could be said that The skin controls the filtration rate of the drug. Of all ways, as the skin as such is not part of the present invention, the behavior of the skin in connection with the supply of the Transdermal drug will not be analyzed in detail. Also is okay accepted in the art that when properties are attributed speed controllers to a transdermal device will understand properties associated with the release rate from The device as such. It is also evident that when it is designed a transdermal device to show a certain release behavior, have to be taken into consideration the properties of the skin during the design process.

Hydrogels (used for transdermal matrix and reservoir systems) are materials, which swell when placed in excess of water. They are able to swell quickly and retain a large amount of water in their swollen structure. The materials do not dissolve in water and maintain three-dimensional networks. Hydrogels are usually made of hydrophilic polymer molecules that are crosslinked by chemical bonds or other cohesion forces such as ionic interaction, hydrogen bonds or hydrophobic interaction. Hydrogels are elastic solids in the sense that there are memorized reference configurations to which the system returns even after deforming for a very long time (Park K et al. Biodegradable Hydrogels for Drug Delivery. Technomic Publishing Co., Inc. 1993 ). Examples of hydrogels are polyvinylpyrrolidone and cellulose hydrogels such as methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline (colloidal) cellulose. Other examples are guar gum, gum arabic, agar gum, tragacanth, carrageenan, xanthan gum, algin, carbomer, dextran and chitin.

It may also be possible to manufacture a polymer system without sheets (reinforcing membrane and release liner) consisting of 1, 2 or more polymers in a solvent and drug added and for example plasticizers and enhancers. The polymers could be a mixture of hydrophilic and hydrophobic species. This product should be applied to the skin using an appropriate device where the solvent evaporates and leaves a thin invisible film. This type of system can also be of a multilayer type where the drug could be incorporated in different polymer layers with different release characteristics and / or alternative non-drug layers that could function as a velocity limiting membrane. The outer layer is more preferably hydrophobic to obtain occlusion.

The ability to control speed often It is a very important feature for a device transdermal to deliver the correct amount of drug to the patient at the right time. In this way the maximum effectiveness while minimizing side effects. Many factors influence the ability to control speed of a transdermal device. In the following Table 1 the most important of these factors are listed and their influence is marked in the respective device type. A plus sign indicates that the influence is strong. The absence of a plus sign does not exclude that the Corresponding factor has at least some influence.

TABLE 1 Type of device

2

Taking into account the convenience of carrying a patch as well as the ease of manufacture, the type device Adhesive drug and depot are currently considered as the better ways to make the present transdermal supply of tolterodine

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The devices according to the invention may include one or more filtration enhancing substances transdermal to increase the amount of tolterodine that can penetrate the skin and reach systemic circulation, or to reduce patch size. The appropriate enhancers in the The present invention can be categorized into the following groups, although enhancers that do not belong to any of these groups  They are not excluded.

- alcohols , such as short chain alcohols, for example, ethanol and the like, long chain fatty alcohols, for example, lauryl alcohols, and the like, and polyalcohols, for example propylene glycol, glycerin and the like;

- amides , such as amides with long aliphatic chains, or aromatic amides such as N, N-diethyl-m-toluamide;

- amino acids ;

- azone and azone compounds ;

- essential oils , that is, essential oils or constituents thereof, such as 1-carvone, 1-menthol-menthol, and the like;

- fatty acids and fatty acid esters , such as oleic acid, lauric acid and the like, additional fatty acid esters, such as isopropyl myristate, and various esters of lauric acid and oleic acid and the like;

- macrocyclic compounds , such as cyclopentadecanone and cyclodextrins;

- phospholipids and phosphate compounds , such as phospholipids;

- 2-pyrrolidone compounds ; Y

- varied compounds , such as sulfoxides, such as dimethylsulfoxides, and fatty acid ethers, such as Lauret-9 and polyoxylauryl ether.

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Combinations of different enhancers groups in the previous categorization can be very useful and effective.

For a global view of the enhancers, see additionally, for example, Santus GC et al. Transdermal enhancer patent literature. J Control Release 1993; 25: 1-20, and Smith EW et al. Percutaneous penetration enhancers CRC Press Inc. 1995.

Detailed description of the invention Materials and devices used in the examples materials Drug

Tolterodine base were supplied, Tolterodine L-Tartrate and DD 01 by Pharmacia & Upjohn (Uppsala, Sweden).

Polymers

Eudragit RL 30D, Eudragit RL were supplied 100 and Röhm 2787F by Röhm GmbH Chemische Fabrik, was supplied Polividona 90 by BASF, MA-24 era of Adhesives Research, Inc., PSA-9839 silicone adhesive was from NuSi Technology and Durotak were supplied 387-2052, 387-2054, 387-2287, 387-2516, 387-2353, 387-2825, 387-2620, 87-2070 and 87-2852 by National Starch & Chemical.

Plates

Polyester release coatings siliconized (S 2016 and FL2000-696029 / 3) se obtained from Rexam Release, the release liner fluoropolymer coated (Scotchpak 1022), the membranes of reinforcement (Scotchpak 1012 and 1109) and CoTran membranes (with 9% and 19% vinyl acetate (VA) respectively) were obtained all of 3M Corp. The non-occlusive reinforcing membrane (membrane of 0.2 mm PVDF "Emflon 11") was from Pall Specialty Materials

Other materials

Sodium hydroxide was supplied, disodium hydrogen phosphate, Tween 80, ethyl acetate and propylene glycol by Merck. Triethyl acetate was supplied by Fluka, methyl laurate (Estol 1507) by Unichema and ethanol 99.9% by Danisco Distillers.

Patch Formulation Studies

The patches were prepared by dissolving the tolterodine base directly in the polymers or by dissolving it in a solvent before adding the polymer. Gel coating Drug was performed using:

one)

a coating equipment (RK Print Coat Instr. LTD, coating Type KCC control 202) or

2)

a Laboratory Coater (Pagendarm, Type RAM 300).

After drying, a layer of adhesive to any of the formulations producing a laminate of adhesive drug (without extra adhesive layer) or a multi-laminate (with extra adhesive layer).

Deposit formulation study

Tolterodine base was dissolved in ethanol and propylene glycol. Methyl laurate was added and the solution was then it was filled in deposit patches by the use of a machine deposit (A&D, GmbH, Type PF-80).

Determination by quantitative HPLC of the content of tolterodine Procedure used for Example 3

The content of tolterodine base in patches It was determined using an HPLC procedure. The system consisted of a 2248 pump from HPLC Pharmacia LKB, an automatic sampler Marathon-XT, a detector of UV-visible 2141 Pharmacia LKB and as a system of data processing Hewlett Packard Vectra VL2 PC was used with EZ-chrom software. The Nucleosil C18 5 column um 120 x 4 mm d.i. It was from Phenomenex.

The mobile phase consisted of 0.1 M phosphate buffer pH 2.5: acetonitrile (680: 320, v / v). The flow rate was 1.0 ml / min, the UV detection was performed at 280 nm and the injection volume was 20 \ mul.

Procedure used for Examples 5, 6, 9, 12, 14, 15, 19 and 37

The content of tolterodine base in patches It was determined using an HPLC procedure. The system consisted of a 2248 pump from HPLC Pharmacia LKB, an automatic sampler Marathon-XT, a UV-visible detector 2141 Pharmacia LKB and as a data processing system was used Hewlett Packard Vectra VL2 PC with EZ-chrom software.  The Nucleosil C18 5 µm 150 x 4.6 mm column d.i. It was from Phenomenex

The mobile phase consisted of 0.05 M phosphate buffer pH 2.5: acetonitrile (550: 450, v / v). The flow rate was 1.0 ml / min, the UV detection was performed at 285 nm and the injection volume was 50 \ mul.

Procedure used for Example 25

The content of DD 01 in the patches is determined using an HPLC procedure. The system consisted of a 2248 Pharmacia LKB HPLC pump, an automatic sampler Marathon-XT, a UV-visible detector 2141 Pharmacia LKB and as a data processing system was used Hewlett Packard vectra VL2 PC with EZ-chrom software.  The Nucleosil C18 5 µm 150 x 4.6 mm column was Phenomenex

The mobile phase consisted of 0.05 M phosphate buffer pH 2.5: acetonitrile (600: 400, v / v) with 1.0 g of acid octanosulfonic / 1000 ml. The flow rate was 1.0 ml / min, the UV detection it was performed at 280 nm and the injection volume was 50 µl.

In vitro dissolution studies

In vitro dissolution studies were performed according to USP 23, p. 1797 (Apparatus 5, disk-to-blade procedure). The system consisted of a six-vessel Pharma Test Type PTW S3C dissolution apparatus. 600 ml (500 ml for Example 4) of 0.05 M phosphate buffer, pH 7.4 equilibrated at 32 ± 0.5 ° C was used as the dissolution medium. Samples were periodically withdrawn and measured by HPLC.

For Examples 30 and 38 the apparatus was modified by the use of a convex screen (TDS-CR) to keep transdermal systems in position during test.

In vitro skin filtration studies

In vitro skin filtration results were obtained from studies in pig or human skin using Franz diffusion cells.

Full thickness human or pig skin was used (used in Example 1) or 765 µm skin (used in all other examples). The 765 µm skin was isolated using a dermatome (Zimmer Electric Dermatome 8821, Zimmer Chirurgie).

The skin was mounted on diffusion cells with an available diffusion area of 1.8 cm2. The inner side of the skin was exposed to 12.1 ml of the receptor phase (0.05 phosphate buffer M, pH 7.4) at 37 ± 1 ° C. Samples were periodically removed and were measured by HPLC. The flows (\ mug / cm2 / h) were obtained by linear regression of the data in stationary phase.

Examples Example 1

In vitro skin filtration studies of tolterodine base solutions.

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Solution one

240 mg of tolterodine base was dissolved in 20 ml of propylene glycol.

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Solution 2

240 mg of tolterodine base was dissolved in 20 ml of ethyl acetate

In vitro skin filtration of tolterodine base of solution 1 and 2 respectively through full-thickness pig skin was investigated using Franz diffusion cells. For tolterodine base in solution 2, full thickness human skin was also used. The cumulative amount of tolterodine base in the receptor solution versus time is shown in Fig. 2. An increase in the amount of tolterodine base is observed in the following order: ethyl acetate> propylene glycol. The results show that it should be possible to adjust the flow through the skin by changing the solvent.

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Example 2

In vitro filtration studies through synthetic membranes and pig skin with dermatome based tolterodine solutions, which mimic the transdermal deposit-type device. Enhancer was added to one of the solutions.

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Solution 3

0.5 g of tolterodine base in 9.5 g of 1% hydroxypropylcellulose (HPC) / ethanol.

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Solution 4

0.5 g of tolterodine base in 9.5 g of HPC at 3% / ethanol.

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Solution 5

0.5 g of tolterodine base in 9.5 g of laurate methyl: ethanol (1: 9).

In vitro cutaneous filtration of tolterodine base of solutions 3, 4 and 5 through 2 different synthetic membranes using Franz diffusion cells was investigated. Membranes of the following types were used: CoTran 9702 (microporous polyethylene film) with 9% vinyl acetate (VA) and CoTran 9728 with 19% vinyl acetate. Solutions 3 and 4 were both applied on the surface of the two mentioned membranes while solution 5 was only applied on the surface of the CoTran 9702 membrane with 9% vinyl acetate. The membranes were placed on top of pig skin with dermatome. The internal sides of the pig skin were exposed to 12.1 ml of receptor solution (0.05 M phosphate pH 7.4 equilibrated at 37 ± 1 ° C).

The cumulative amount of tolterodine base in the receiver solution versus time is shown in Fig. 3. The flows were approximately 4 µg / cm 2 / h when the CoTran membrane with 1 or 3% HPC and 9% VA, approximately 11 ? / cm2 / h when CoTran membrane was used with HPC at 1 o 3% and VA 19% and 9 µg / cm 2 / h when the membrane was used CoTran with enhancer and VA at 9%. The results show that it is possible to control the release rate of tolterodine base from a deposit type device by changing the membrane. It was also observed that when enhancer was added a major flow

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Example 3 System 1 (adhesive drug, acrylate) Loading of different acrylates with tolterodine base

5 g of tolterodine base was dissolved in 11 g of ethanol and added to 20 g of Durotak 387-2287. The drug gel was coated on a reinforcing membrane (Scotchpak 1012) using the coating equipment. The thickness of the wet layer was 400 µm. The laminate was dried for 20 min. to TA and then for 30 min. at 40 ° C. A coating of Polyester release (S 2016) on the dried drug gel. The sheet was cut into patches and stored at 2-8 ° C until use (packed in Barex bags). The concentration of Tolterodine base in the patches was 2.5 mg / cm2.

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System 2 (multi-laminate, acrylate) (Comparative)

5 g of tolterodine base was dissolved in 10 ml of ethanol A mixture of 6.4 g of Eudragit RL 100 and 6.4 g was added ethanol and a mixture of 2.6 g Polividone 90 and 10.2 g of ethanol Tolterodine solution based on ethanol. 4 g was added at the end of propylene glycol. The drug gel was coated on a membrane reinforcement (Scotchpak 1109) using the coating equipment. He thickness of the wet layer was 400 µm. The laminate was dried at 40 ° C for 2 hours. An adhesive layer consisting of Plastoid E35H it was coated on a polyester film (S 2016) and dried to 80 ° C for 10 min. The 2 layers were subsequently laminated. The sheet was cut into patches and stored at 2-8 ° C until use (packed in Barex bags). The concentration of Tolterodine base in the patches was 2.0 mg / cm2.

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System 3 (multi-laminate, acrylate based on water) (Comparative)

1 g of tolterodine base was mixed with Tween 80 heating at 60-70 ° C. 1.8 g of acetate were added of triethyl and 1.3 g of desm. To the mix. The final mix then it was added to 25 g of Eudragit RL 30 D. In the end they were added 180 mg of 1 N NaOH. The drug gel was coated on a membrane. reinforcement (Scotchpak 1109) using the coating equipment. He thickness of the wet layer was 400 µm. The laminate was dried at 40 ° C for 2 hours. An adhesive layer consisting of Plastoid E35H it was coated on a polyester film (S2016) and dried to 80 ° C for 10 min. The 2 layers were subsequently laminated. The sheet was cut into patches and stored at 2-8 ° C until use (packed in Barex bags). The concentration of Tolterodine base in the patches was 0.5 mg / cm2.

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Example 4

In vitro dissolution studies of transdermal drug delivery Systems 1 and 2 according to Example 3 (Fig. 4).

7.1 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the surface Release up. Samples were taken periodically up to 24 hours The amount of tolterodine base in the samples is determined by HPLC and the amount of tolterodine base released from the patches were expressed in mg of tolterodine base per cm2. He result shows that it is possible to control the speed of Tolterodine base release by changing the type of polymer.

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Example 5 System 4 (drug in adhesive, acrylates) Loading acrylates with tolterodine base in different concentrations (same dry coating weight)

Patches containing different Tolterodine base concentrations in Durotak 387-2052 (1), 387-2054 (2), 387-2287 (3-7 incl.), 387-2353 (8), 87-2070 (9-12 incl.), 387-2516 (13-15 incl.), 387-2620 (18), 387-2825 (19), 87-2852 (20.21) and Röhm 2787F (24.25).

The figures in parentheses refer to the formulation numbers mentioned in Table 2.

Durotak 387-2052, 387-2054, 387-2287; 387-2353, 87-2070 and 387-2825:

Tolterodine base was dissolved in ethyl acetate then the acrylate polymer was added.

Durotak 387-2516, 387-2620, 87-2852 and Röhm 2787F:

Tolterodine base was dissolved in the polymer of acrylate

The drug gels were coated each on a polyester release liner (S 2016 or FL 2000-696029 / 3) using the coating equipment. He The laminate was dried at 80 ° C (Röhm 2787F dried at 60 ° C) for 10 min. The dry coating weight was approximately 110 g / m2. A reinforcing membrane was laminated (Scotchpak 1109) on the dried drug gel. The sheets were cut into patches and They were stored at 2-8ºC until use (packed in Barex bags).

See the following Table 2 for information about the amount of ingredients and concentration of tolterodine  Patches base.

TABLE 2 Amount of ingredients and concentration of tolterodine

4

Example 6 System 5 (adhesive drug, polyisobutylene) Loading polyisobutylene with tolterodine base in two different concentrations (same dry coating weight)

Patches containing tolterodine were manufactured base on MA-24 (22,23).

The figures in parentheses refer to the formulation numbers mentioned in Table 2 above.

Tolterodine base was dissolved in ethyl acetate then the polymer MA-24 was added.

The drug gel was coated on a polyester release liner (S 2016) using the equipment Coating. The laminate was dried at 80 ° C for 10 min. The weight Dry coating was approximately 110 g / m2. Be laminated a reinforcing membrane (Scotchpak 1109) on the gel dry drug The sheets were cut into patches and stored at 2-8ºC until use (packed in Barex bags).

See Table 2 above for information. about the amount of ingredients and the concentration of Tolterodine base in patches.

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Example 7

In vitro dissolution studies of transdermal drug delivery Systems 4 and 5 according to Examples 5 and 6 (Fig 5-9). Formulations No. 1-13 incl. and 18-19 (Table 2).

10 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the face of release up. Samples were taken periodically up to 24 hours The amount of tolterodine base in the samples is determined by HPLC and the amount of tolterodine base released from the patches were expressed in mg of tolterodine base per cm2. May be observed from the results that can be obtained different release profiles using different polymers. It can also be seen that within each polymer it is possible obtain different release profiles by varying the concentration.

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Example 8

In vitro skin filtration studies of transdermal drug delivery Systems 4 and 5 according to Examples 5 and 6 (Fig. 10-14). Formulations No. 1-13 incl. and 18-19 (Table 2).

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of tolterodine base in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the receptor solution versus time is shown in Fig. 10-14 The flows are in the range of 0.1-5.5 µg / cm2 / h. From the results it can be seen that different flows can be obtained using different polymers. It can also be seen that obtain higher flows with higher concentrations of tolterodine based on the experiments performed.

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Example 9 System 6 (adhesive drug, acrylate) Acrylate loading with different dry coating weights with the same concentration of tolterodine base in all patches

Patches with tolterodine base were manufactured in Durotak 87-2070 (the coating weights were of approximately 50, 75 and 110 g / m2 respectively) according with System 4, Example 5.

See the following Table 3 for information about the amount of ingredients, coating weights and Tolterodine base concentration in patches.

TABLE 3 Ingredients, coating weights and concentration of tolterodine

5

Example 10

In vitro dissolution studies of the transdermal drug delivery system 6 according to Example 9 (Fig. 15).

10 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the surface Release up. Samples were taken periodically up to 24 hours The amount of tolterodine base in the samples is determined by HPLC and the amount of tolterodine base released from the patches were expressed in mg of tolterodine base per cm2. The results showed that different profiles of release varying the coating weight. It can be seen that the highest release of tolterodine base is obtained with the lowest coating weight

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Example 11

In vitro skin filtration studies of the transdermal drug delivery system 6 according to Example 9 (Fig. 16).

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of tolterodine base in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the receiver solution versus time is shown in Fig. 16. The flows are in the range of 1.3-4.7 \ mug / cm2 / h. It can be seen from the results that different flows can be obtained using different weights of coating. It can also be seen that the greatest flow is gets with the lowest coating weight.

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Example 12 System 7 (adhesive drug, acrylates) Comparison of Durotak 387-2287 with and without crosslinker (XL) added

Patches with tolterodine base were manufactured in Durotak 387-2287 according to System 4. Durotak 2287 does not contain XL per se but in this experiment it They added two different concentrations of XL.

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Addition of 0.5% polybutyl titanate (PBT) to Durotak 387-2287

0.33 g of PBT was dissolved in 5.2 g of heptane 36.0 g of ethanol were added to 130.8 g of Durotak 387-2287 The mixture of ethanol and Durotak 387-2287 was heated to approximately 60 ° C after XL mixture was added.

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Addition of 1.0% PBT to Durotak 387-2287

0.64 g of PBT was dissolved in 10.0 g of heptane 34.4 g of ethanol were added to 124.8 g of Durotak 387-2287. The mixture of ethanol and Durotak 387-2287 was heated to approximately 60 ° C after XL mixture was added.

The concentration of tolterodine base in the patches was about 2 mg / cm2 and the weight of coating was about 100 g / m2.

See the following Table 4 for information about the amount of ingredients, type of crosslinkers, and Tolterodine base concentration in patches.

TABLE 4 Ingredients, type of crosslinker and concentration of tolterodine

6

Example 13

In vitro dissolution studies of the transdermal drug delivery system 7 according to Example 12 (Fig. 17).

10 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the surface Release up. Samples were taken periodically up to 24 hours The amount of tolterodine base in the samples is determined by HPLC and the amount of tolterodine base released from the patches were expressed in mg of tolterodine base per cm2. The results show that the same profiles are obtained from dissolution regardless of the crosslinker added. Can be important to add crosslinking agents to formulations for obtain optimum adhesiveness and cohesion.

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Example 14 System 8 (adhesive drug, acrylate) Acrylate filler with L-tartrate tolterodine

The gels were prepared by suspending the Tolterodine L-tartrate in Durotak polymer 387-2287. A solution of 9.4 M NaOH (in water) corresponding to 2 equimolar to some of the gel to try Turn tartrate into base. A solution of 9.4 M NaOH (in water) to tolterodine base / Durotak gel 387-2287 to assess whether the dissolution profile It changed with the addition of NaOH.

The patches were coated according to the System 4, Example 5.

See Table 5 below for information. about the amount of ingredients, and the concentration of Tolterodine L-tartrate in patches.

TABLE 5 Ingredients and concentration of Tolterodine L-Tartrate

7

Example 15 System 9 (adhesive drug, polyisobutylene) Loading polyisobutylene with L-tartrate tolterodine

The gels were prepared by suspending the Tolterodine L-tartrate in the polymer MA-24 A solution of 9.4 M NaOH (in water) corresponding to 2 equimolar to some of the gel to convert the Tartrate based.

The patches were coated according to the System 5, Example 6.

See Table 5 above for information. about the amount of ingredients and concentration of Tolterodine L-tartrate in patches.

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Example 16

In vitro dissolution studies of transdermal drug delivery Systems 8 and 9 according to Examples 14 and 15 (Fig. 18 and 19). Laminate No. 5 according to Example 5 containing the tolterodine base in Durotak 387-2287 was used for comparison.

10 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the surface Release up. Samples were taken periodically up to 24 hours The amount of tolterodine (calculated as base) in The samples were determined by HPLC and the amount of tolterodine base released from patches was expressed in mg of tolterodine base by cm2. The results show that it is possible to convert the largest part of tolterodine L-tartrate in tolterodine base when NaOH is added to the gel it contains Tolterodine and polymer L-tartrate.

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Example 17

In vitro skin filtration studies of transdermal drug delivery Systems 8 and 9 according to Example 14 and 15 (Fig. 20 and 21).

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of tolterodine (calculated as base) in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the Receiving solution versus time is shown in Fig. 20 and 21. The results show that it is possible to convert most of the Tolterodine L-tartrate in tolterodine base when NaOH is added to the gel containing L-tartrate of tolterodine and polymer.

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Example 18

Stability studies were conducted on the Formulations No. 1, 2, 6, 8, 13, 18 and 19 according to Example 5. The patches were stored at 25 ° C / 60% RH and 40 ° C / 75% RH and the Quantitative determination of tolterodine base was made by HPLC after 0, 1, 2 and 3 months. The results are shown in the Next Table 6. It can be seen that the formulations are stable after 3 months of storage. However, it can a slight decrease in tolterodine content is observed base after 3 months for Durotak 387-2353.

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TABLE 6 Stability of tolterodine base in different Durotak polymers

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Example 19 System 10 (adhesive drug, acrylates). Scale increase of the formulation Acrylate charge with tolterodine base

Patches containing tolterodine were manufactured Durotak base 387-2516 (formulations 16 and 17 according to Table 2).

Tolterodine base was dissolved directly in the Durotak polymer 387-2516.

The drug gel was coated on a polyester release liner (FL 2000-696029 / 3) using the Laboratory Coater. The laminate was dried at 40/80/80 ° C for 10 min. The weight of Dry coating was approximately 110 g / m2. Be laminated a reinforcing membrane (Scotchpak 1109) on the gel dried drug. The laminate was cut into patches and stored at 2-8ºC until use (packed in Barex bags).

See Table 2 above for information. about the amount of ingredients and concentration of tolterodine  Patches base.

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Example 20

In vitro dissolution studies of the transdermal drug delivery system 10 (formulation No. 17 according to Example 19 (Fig. 22). Laminate No. 13 according to Example 5 containing tolterodine base in Durotak 387-2516 was used (laboratory scale) for comparison.

10 cm2 patches were applied to the disk assembly using a suitable adhesive with the surface of  release up. Samples were taken periodically up to 24 hours The amount of tolterodine base in the samples is determined by HPLC and the amount of tolterodine base released from the patches were expressed in mg of tolterodine base per cm2. The results show that the same profiles are obtained from dissolution (regardless of whether the patches are manufactured in laboratory scale or in the Laboratory Coater).

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Example 21

In vitro skin filtration studies of the transdermal drug delivery system 10 (laminate No. 17) according to Example 19 (Fig. 23). Formulation No. 13 containing tolterodine base in Durotak 387-2516 (laboratory scale) was used for comparison.

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were removed up to 48 hours. The amount of tolterodine base in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the receiver solution versus time is shown in Fig. 23. The results show that the same profiles are obtained (regardless of whether the patches are manufactured in scale of laboratory or in the Laboratory Coater).

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Example 22

In vivo skin filtration studies of the transdermal drug delivery system 10 according to Example 19 (Formulation No. 16, Table 2).

In vivo skin filtration of tolterodine base (1 person) was investigated. The 10 cm2 patch was applied over the upper arm for 24 hours after the residual amount of tolterodine base in the patch was analyzed. The result showed that approximately 4.8 mg of tolterodine base was released, corresponding to approximately 7.2 mg of tolterodine L-tartrate in the patch and therefore penetrated the skin.

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Example 23

Study of primary skin irritation in rabbit and assay for delayed contact hypersensitivity using the Cobaya Maximization Test (performed by Scantox, Denmark).

The primary irritant effect of tolterodine base and tolterodine L-tartrate was investigated according to the procedure in OECD Guideline No. 404, "Acute Dermal Irritation / Corrosion", 1992, and EEC Guideline B.4 "Acute Toxicity ( skin irritation) ", 29.12.1992 with the modification that the exposure time in both cases was 24 hours.

0.5 g of each test material was moistened with 0.5 ml of distilled water and applied to the rabbit. After After 24 hours the treated skin was cleaned and after 1, 24, 48 and 72 additional hours the skin reactions were read. It was found that for tolterodine base the average value was 0.1 for erythema and 0.0 for edema while for L-tartrate Tolterodine the average value was 0.0 for both erythema and edema.  This means that the two tolterodine base compounds and Tolterodine L-Tartrate should not be classified as  skin irritants

Sensitization potential was investigated dermal of tolterodine L-tartrate according to one of the procedures recommended in the OECD Guidelines Nº 406, "Skin Sensitization", 1992 and the ECC Guideline "EEC 92/69 part 6B ", 1992. The contact hypersensitivity test delayed was the Cobaya Maximization Test described by B. Magnusson and A.M. Kligman

A concentration of the test article was used 1% (w / w) in sesame oil for intradermal induction. Be used a concentration of the test article of 25% (w / w) in oil sesame for topical induction and for the application of stimulation

It was concluded that L-tartrate Tolterodine did not cause a hypersensitivity reaction due to delayed contact in guinea pigs.

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Example 24

Study of primary skin irritation in rabbit (performed by Scantox, Denmark).

The primary cutaneous irritant effect of tolterodine base patches of 1 mg / cm2, 1.5 mg / cm2 and 2 mg / cm2 was investigated using Durotak 387-2516 (formulations No. 13 + 14 + 15) and placebo patches Durotak 387-2516 (same coating weight as for active laminates) according to the procedure in OECD Guideline No. 404, "Acute Dermal Irritation / Corrosion", 1992, and EEC Guideline B. 4 "Acute Toxicity (skin irritation)", 29.12.1992.

Tolterodine base patches were applied and placebo to rabbits. After 4 hours of exposure it the test items were removed and the skin was examined 1, 24, 48 and 72 hours and up to 7 days after the end of the exhibition. Be found that for the 1 mg / cm2 base tolterodine patches and 1.5 mg / cm2 the average value was 0.1 for erythema and 0.0 for edema while for tolterodine patches base of 2 mg / cm2  and placebo the mean values were 0.2 for erythema and 0.1 for edema. This means that the tolterodine patches base of 1 mg / cm2, 1.5 mg / cm2 and 2 mg / cm2 should not be classified as skin irritants.

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Example 25 System 11 (DD 01 in drug in adhesive, acrylate)

3.8 g of DD 01 were added to 90 g Durotak 387-2516 and 3 ml of ethanol and homogenized for 5 min. The drug gel was coated on a coating Polyester release (FL 2000-696029 / 3) using The coating equipment. The laminate was dried at 80 ° C for 10 min. The dry coating weight was approximately 110 g / m2. A reinforcing membrane (Scotchpak 1109) was laminated on The dried drug gel. The sheets were cut into patches and stored at 2-8ºC until use (packaged in Barex bags). The concentration of DD 01 in the patches was 0.91 mg / cm2.

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Example 26

In vitro dissolution study of the transdermal delivery system 11 according to Example 25 (Fig. 24).

10 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the surface Release up. Samples were taken periodically up to 24 hours The amount of DD 01 in the samples was determined by HPLC and the amount of DD 01 released from the patches was expressed in mg of DD 01 per cm2. From the results you can Note that approximately 30% of DD 01 is released from the patch after 24 hours

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Example 27

In vitro skin filtration study of the transdermal drug delivery system 11 according to Example 25 (Fig. 25).

In vitro skin filtration of DD 01 through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of DD 01 in the samples was determined by HPLC.

The cumulative amount of DD 01 in the solution receiver versus time is shown in Fig 25. The flow obtained was 2 µg / cm2 / h and the amount of DD 01 that penetrated the skin was about 7%.

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Example 28 System 12 (multi-laminate, acrylate) (Comparative)

Layer b: 6 g of tolterodine base was dissolved in 69 g of Durotak 387-2516. The drug gel is coated on a release liner (FL 2000-696029 / 3) using the coating equipment. He laminate was dried at 80 ° C for 10 min. The coating weight in dry was about 50 g / m2. A membrane of reinforcement (Scotchpak 1109) on the dried drug gel. Later removed the release liner and a membrane was laminated speed control (CoTran 9728-Acetate 19% vinyl) on the dried drug gel. Concentration theoretically calculated (not analyzed) of tolterodine base in the Laminate was 0.8 mg / cm2.

Layer a: 6 g of tolterodine base was dissolved in 93 g of Durotak 87-2852. The drug gel was coated on a release coating (FL 2000-696029 / 3) using the coating equipment. The laminate was dried at 80 ° C for 10 min. The dry coating weight was about 50 g / m2 and the theoretically calculated (unanalyzed) concentration of tolterodine base in the laminate was 0.8 mg / cm2. Then layer a was laminated to layer b. Layer b
then it was the layer closest to the reinforcing membrane while layer a was the outer layer.

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Example 29 System 13 (multi-laminate, acrylate) (Comparative)

Layer b: 6 g of tolterodine base was dissolved in 93 g of Durotak 87-2852. The drug gel is coated on a release liner (FL 2000-696029 / 3) using the coating equipment. He laminate was dried at 80 ° C for 10 min. The coating weight in dry was about 50 g / m2. A membrane of reinforcement (Scotchpak 1109) on the dried drug gel. Later removed the release liner and a membrane was laminated speed control (CoTran 9728-Acetate 19% vinyl) on the dried drug gel. Concentration theoretically calculated (not analyzed) of tolterodine base in the Laminate was 0.8 mg / cm2.

Layer a: 6 g of tolterodine base was dissolved in 69 g of Durotak 387-2516. The drug gel is coated on a release liner (FL 2000-696029 / 3) using the coating equipment. He laminate was dried at 80 ° C for 10 min. The coating weight in dry was about 50 g / m2 and the concentration theoretically calculated (not analyzed) of tolterodine base in the laminate was 0.8 mg / cm2. Then the layer a was laminated to the layer b. Then layer b was the layer closest to the membrane of reinforcement while layer a was the outer layer.

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Example 30

In vitro dissolution studies of transdermal drug delivery Systems 12 and 13 according to Example 28 and 29 (Fig. 26).

10 cm2 patches were applied to the convex screen, with the release surface facing up. Be Samples were taken periodically up to 24 hours. The amount of Tolterodine base in the samples was determined by HPLC and the amount of tolterodine base released from the patches was expressed in mg tolterodine base per cm2. The results show that it is possible to vary the release profile by changing the polymers in The multi-laminated patch.

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Example 31

In vitro skin filtration study of transdermal drug delivery Systems 12 and 13 according to Example 28 and 29 (Fig. 27).

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of tolterodine base in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the receptor solution versus time is shown in Fig 27. The results show that it is possible to vary the release profile by changing the polymers in the multilaminate patch.
do.

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Example 32 System 14 (adhesive drug, silicone)

4.5 g of tolterodine base was dissolved in 46 g from PSA-9839. The drug gel was coated on a polyester release liner (Scotchpak 1022) using the coating equipment The laminate was dried at 50 ° C for 10 min. The dry coating weight was approximately 150 g / m2. A reinforcing membrane was laminated (Scotchpak 1109) on the dried drug gel. The sheets were cut into patches and They were stored at 2-8ºC until use (packed in Barex bags). The theoretical concentration (not analyzed) of Tolterodine base in the patches was 1.5 mg / cm2.

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Example 33

In vitro dissolution study of the transdermal delivery system 14 according to Example 32 (Fig. 28).

10 cm2 patches were applied to the disk assembly, using a suitable adhesive, with the surface Release up. Samples were taken periodically up to 24 hours The amount of tolterodine base in the samples is determined by HPLC and the amount of tolterodine base released from the patches were expressed in mg of tolterodine base per cm2. Starting of the results it can be seen that tolterodine base completes It was released after 8 hours.

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Example 34

In vitro skin filtration study of the transdermal drug delivery system 14 according to Example 32 (Fig. 29).

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of tolterodine base in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the receiver versus time solution is shown in Fig 29. The obtained flow was 7 µg / cm2 / h and the amount of Tolterodine base that penetrated the skin was approximately 17% (calculated from the theoretically calculated amount of tolterodine base in the patch).

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Example 35 System 15 (adhesive drug, acrylate, reinforcing membrane not occlusive)

1 g of tolterodine base was dissolved in 20 g of Durotak 387-2516. The drug gel was coated on a polyester release liner (FL 2000-696029 / 3) using the coating equipment. He laminate was dried at 80 ° C for 10 min. The coating weight in dry was about 115 g / m2. A membrane was laminated of non-occlusive reinforcement (PVDF of 0.2 µm "Emflon 11") on The dried drug gel. The sheets were cut into patches and stored at 2-8ºC until use (packaged in Barex bags). Theoretically calculated concentration (no analyzed) Tolterodine base in patches was 1.0 mg / cm2.

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Example 36

In vitro skin filtration study of the transdermal drug delivery system 15 according to Example 35 (Fig. 30).

In vitro skin filtration of tolterodine base through pig skin with dermatome was investigated using Franz diffusion cells. Samples were taken periodically up to 48 hours. The amount of tolterodine base in the samples was determined by HPLC.

The cumulative amount of tolterodine base in the receiver versus time solution is shown in Fig 30. The obtained flow was 0.1 µg / cm2 / h and the amount of Tolterodine base that penetrated the skin was approximately 0.4% (calculated from the theoretically calculated amount of tolterodine base in the patch). That is, only a quantity very small tolterodine penetrates the skin compared to when an occlusive reinforcement membrane is used.

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Example 37 System 16 (Deposit Patch)

7 g of tolterodine base was dissolved in 65 g of ethanol then 65 g of propylene glycol and 3.5 g of methyl laurate 750 µl were filled in each deposit patch using the deposit machine. As a reinforcing membrane was used Scotchpak 1012 and as a speed control membrane was used CoTran 9702-9% Vinyl Acetate). Not applied adhesive to the deposit patch. Tolterodine base concentration  in the deposit patches it was 1.4 mg / cm2.

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Example 38

In vitro dissolution study of the transdermal drug delivery system 16 according to Example 37 (Fig. 31).

30 cm2 deposit patches were applied to the convex screen using a placebo drug patch in 50 cm2 adhesive made of Durotak 387-2287, with the release surface facing above. Samples were taken periodically up to 24 hours. The amount of tolterodine base in the samples was determined by HPLC and the amount of tolterodine base released from the patches was expressed in mg of tolterodine base per cm2. The result shows that the 15% of tolterodine base was released after 24 hours.

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Example 39

Patch bioavailability study Tolterodine base transdermal (1.79 mg / cm2). A study of dose scale, simple sequence, open in 8 volunteers healthy (Fig. 32).

The clinical study was conducted in Quintiles Phase I Clinic, Uppsala, Sweden. Each subject started with a patch of 15 cm2. After a two week elimination period, the Subjects continued with a 30 cm2 patch. The patches are applied on the dorsal side of the upper arm during 36 hours later the residual amount of tolterodine base was analyzed in the patch Blood samples were taken for determination of tolterodine base and metabolites before the dose and during the 36 hours the patches were applied to the subjects. The blood sampling results are shown in Fig. 32. It noted that an apparent steady state was reached approximately 24 hours after application.

The results of the quantity analysis Tolterodine base residual in patches showed that it approximately 4.8 mg of tolterodine base was released from the patches from the 15 cm 2 patch and about 10.6 mg of tolterodine base from the 30 cm2 patch (corresponding to 7.2 and 15.9 mg of tolterodine tartrate respectively) and per both penetrated the skin.

The previous examples show that it is possible administer tolterodine and control its release rate using all known types of devices for administration of transdermal drug Other tolterodine salts could be used different from tartrate to obtain the desirable effect since it knows that other different tartrate anions can generate pairs ionic with more favorable skin filtration rates.

Various vehicles and means can be used to tolterodine in transdermal administration. One of sayings vehicles is cyclodextrin, especially β-cyclodextrin. Tolterodine can bind in the cyclodextrin cavities to form the so-called inclusion complexes The binding of tolterodine to a cyclodextrin leads to increased supply speed or speed of supply decreased depending on the proportion tolterodine-cyclodextrin.

The data in Fig. 10-13 show that an apparent order 0 supply of tolterodine through the skin for approximately 5 to 48 hours. During that period, only approximately 10% of the loaded amount of drug in the devices and therefore this order supply speed 0 can be maintained at least until 7 days. Such a patch once a week will greatly improve the patient compliance, which is important since patients Elders often use tolterodine.

It may be desirable to use higher dosages of drug during the day or night, depending on the time The overactive bladder is more problematic. It belongs to the present invention administer tolterodine in such a way that a therapeutically effective systemic level of tolterodine to a degree older during the day or night. The previous objective can be get by applying the transdermal device at the moment appropriate during the day or night in combination with the design of the device with the appropriate release profile. Same thing happens for a device designed to deliver tolterodine to a degree lower during the day or night.

Dosage

The required input speed (Ro) of tolterodine from a transdermal formulation can be exemplified by the following estimate for a bad metabolizer. The systemic elimination (CL) is approximately 10 l / h and the average serum concentration (C) after tolterodine 2 mg bid is approximately 10 \ mug / l. (Brynne et al. Clin Pharmacol. Ther. 1998). Therefore, Ro = CL • C = 100 µg / h = 2.4 mg / 24 h-2 \ mug / h / cm2 (assuming the area of almost maximum patch be 50 cm2). The minimum patch area required will be approximately 3 cm2 (assuming a flow rate almost maximum of 35 µg / h / cm2). These estimates show the feasibility of producing transdermal formulations that may be clinically useful.

Based on the pharmacokinetic properties of tolterodine in the population to be treated, the efficacy profile clinical, age range and body weight to cover (including the indication for children) and the formulation properties of patch required, it is mostly expected that the areas of patch are in the range of 3-50 cm2. Be they will build patches for release speeds that vary from 0.2-35 µg / h / cm2. DD 01 will also be used as an alternative to the active ingredient in formulations transdermal

A useful device for administration transdermal tolterodine should have an hourly flow rate of tolterodine of about 0.1 µg / h / cm 2 a about 100 µg / h / cm2, preferably of about 0.2 µg / h / cm 2 to about 35 mug / h / cm 2 and an area of about 2 cm 2 a about 100 cm2, preferably about 5 cm 2 to about 30 cm 2.

Previous release speeds imply that a device for transdermal delivery of Tolterodine should have a tolterodine load of approximately 0.1 mg / cm2 to about 5 mg / cm2.

It should also be contemplated that a device for transdermal delivery for 2 or more days would facilitate additionally the use of the transdermal formulation. it's possible design a device that supplies tolterodine during a predefined period of time, preferably 12, 24 or 48 hours, or even up to 7 or 14 days.

When tolterodine is administered in a transdermal device the latter should preferably be occlusive, which means that the device does not allow it to migrate water out from the skin area covered by the device or at least with a speed lower than the speed of loss of usual water from the skin. This increases hydration. of the skin that favors the penetration of tolterodine through the skin.

For convenience and / or to get an increase faster at the plasma level, it is possible to design a series of Tolterodine formulations, optionally salts that include it, and, the tolterodine metabolite (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine  comprising at least one device for transdermal delivery and at least one formulation for oral, sublingual administration, buccal, nasal, pulmonary, rectal and / or other administration through the mucosa

Claims (11)

1. Device for transdermal administration, characterized in that it administers tolterodine in its isomeric form R, optionally salts which include it and the metabolite of tolterodine (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3 -phenylpropanamine, and optionally together with a pharmaceutically acceptable vehicle (s), to a human being or an animal to achieve an effect against the overactive bladder, and because it is of the type of drug in adhesive or of the type of deposit or combinations of these two types. 2. Device for transdermal administration according to any one of the preceding claims, characterized in that it has a tolterodine load of about 0.1 mg / cm 2 to about 5 mg / cm 2. 3. Device for transdermal administration according to any one of the preceding claims, characterized in that it has an hourly flow rate of tolterodine of about 0.1 µg / h / cm2 to about 100 µg / h / cm ^ 2, preferably from about 0.2 µg / h / cm 2 to about 35 µg / h / cm 2. Device for transdermal administration according to any one of the preceding claims, characterized in that it has an area of about 2 cm 2 to about 100 cm 2, preferably from about 5 cm 2 to about 30 cm2. 5. Device for transdermal administration according to any one of the preceding claims, characterized in that it supplies tolterodine for a predefined period of time, preferably 12, 24 or 48 hours, or up to 7 or 14 days. Device according to any one of the preceding claims, characterized in that tolterodine is present in a complex with cyclodextrin, preferably β-cyclodextrin. 7. Device according to any one of the preceding claims, characterized in that it additionally comprises a substance that enhances transdermal penetration. Device according to any one of the preceding claims, characterized in that it additionally comprises a substance that reduces irritating reactions. 9. Device according to any one of the preceding claims, characterized in that it is occlusive. 10. Use of tolterodine in its isomeric form R, optionally salts that include it and, the tolterodine metabolite (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine and optionally together with pharmaceutical vehicle (s) acceptable (s), for the manufacture of a defined device in claim 1 to be administered transdermally to achieve an effect against overactive bladder and / or symptoms associated with this condition. 11. Use according to claim 10, characterized in that more than one transdermal device is used at the same time.